Contribution of glucocorticoids and insulin resistance to dyslipidemias

Insulin resistance is a central feature of android (visceral) obesity, and it is associated with hypertension, high concentrations of very low density lipoproteins (VLDL) plus low density lipoproteins (LDL), and low concentrations of high density lipoproteins (HDL). Cortisol produces insulin resistance in tissues and increases the sensitivity of adipose tissue to lipolytic hormones. This causes an accelerated release of fatty acids from adipose tissue, and delivery to the liver is particularly large because of the high visceral mass of adipose tissue in android obesity. Fatty acids themselves cause further insulin resistance in the liver, and they stimulate gluconeogenesis and triacylglycerol synthesis. Glucocorticoids and insulin also stimulate fatty acid synthesis synergistically. The increased availabilities of fatty acids and glucocorticoids provide strong stimuli for the secretion of VLDL. Dexamethasone (a synthetic glucocorticoid) stimulates triacylglycerol secretion, and particularly apolipoprotein B (apoB) secretion from isolated hepatocytes. These effects are antagonized by insulin. The mechanisms for the increased secretion of apoB involve increased synthesis and decreased degradation of apoB: effects that are opposite to those of insulin. The increase in apoB secretion means that more VLDL particles are produced under the influence of cortisol. This has atherogenic implications, since each VLDL particle is converted to an intermediate-density-lipoprotein, or to LDL. The uptake of these particles is decreased by glucocorticoids through down-regulation of the hepatic apoB/E receptor. Consequently, insulin resistance and high glucocorticoid activity can produce hyperapo-betalipoproteinemia. This relationship can partly explain the dyslipidemia associated with android obesity, diabetes, and stress, and why these conditions predispose to premature atherosclerosis.